PROJECT SUMMARY Thoracic aortic aneurysms (TAAs) affect young and old males and females and are responsible for significant morbidity and mortality. Findings over recent years suggest that an aberrant activity of or signaling through transforming growth factor-beta (TGF?) plays important roles in TAAs, yet controversy remains regarding the precise mechanisms. This lack of understanding continues to hinder the identification of improved therapeutic approaches as revealed by the recent failure of a highly anticipated clinical trial of losartan, an angiotensin-II receptor antagonist. We and others recently hypothesized that the collection of predisposing genetic mutations suggests that TAAs result, in part, from a compromised cellular mechanosensing and mechanoregulation of the extracellular matrix that endows the aortic wall with its structural integrity. Importantly, TGF? can be viewed, in part, as a critical mechanotransducer ? its production and activation are mechanosensitive and its downstream gene products include the contractile proteins that are fundamental to sensing and regulating the extracellular matrix that is produced in response to its increased signaling. The goal of this project is to test novel hypotheses on interactions among the structural and instructional roles of altered TGF? signaling, smooth muscle cell mechanosensing of altered wall stresses (particularly those due to hypertension, a primary risk factor for TAAs), and the integrity of fibrillin-1, an essential glycoprotein that associates with elastin to form elastic fibers. Towards this end, we will use a combination of new genetically modified mouse models, in vivo models of induced hypertension, and clinical specimens of TAAs. We will characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses (computed by Core C) and disrupted fibrillin-1 that depend on TGF? signaling and lead to maladaptive remodeling of the aortic wall. Finally, this project will complement naturally the other 3 projects in this PPG. The results of our work (Project 4) will extend the characterization of how graded losses of extracellular matrix integrity influence the biological responses, including angiotensin receptor signaling, of TAAs to physiological hemodynamic loads (Project 1), will complement investigations of biomechanical mechanisms that control the activation of TGF? in TAAs (Project 2), and will inform studies of endothelial flow-regulated responses and extracellular matrix remodeling in TAAs (Project 3). As in the other three projects, we will use Core B to elucidate complex systems-level interactions among the mechanical, structural, and biological factors studied. Coordinated via Core A, the findings of this highly integrated PPG will contribute significantly to understanding coupled dysfunctional mechanosensing by aortic cells and identifying new molecular targets to treat TAAs.